Only one locus, termed HLA-DR, has been assigned to human Ia antigens by population and family studies. However, our immunochemical studies have provided evidence for the existence of two new Ia loci, provisionally called DC and BR, closely linked to the DR locus. Accordingly, this proposed research is directed towards the discovery and the structural and functional characterization of allelic products of the DC and Br loci, i.e., DC and BR antigens. The major projects are summarized as follows: The first project is 1) to isolate human Ia antigens from HLA-homozygous lymphoid cell lines by the physicochemical fractionation methods that we have adapted and to separate or enrich the DC and BR antigens by immunospecific negative selection, 2) to define the antigen specificity of DC and BR antigens by the radioimmunoassay procedures that we have developed, using Ia alloantisera and monoclonal antibodies, including those to be made available through the IX International Histocompatibility workshop, and 3) to analyse the structural characteristics of DC and BR antigens by microfingerprinting. The second project is 1) to evaluate the disease association of DC and BR antigens by population and clinical studies and 2) to elucidate the functional implication of DC an BR antigens in antigen recognition by T-cells by testing the influence of DC or BR compatibility (or incompatibility) and the blocking effect of anti-DC or BR antibodies on T-cell proliferative responses. In order to facilitate these projects, we also plan 1) to produce monoclonal or polyclonal antibodies by using purified DR, DC, BR antigens or their subunits and 2) to make polyspecific Ia alloantisera monospecific by appropriate absorption procedures. These studies will enable us to establish the multiple loci control of human Ia antigens and the correlation of human Ia antigens with immune response gene products and eventually lead us to the recognition and isolation of functional receptors and effectors involved in human immune responses.